Multiset Statistics for Gene Set Analysis.
Ontology highlight
ABSTRACT:
SUBMITTER: Newton MA
PROVIDER: S-EPMC4405258 | biostudies-literature | 2015 Apr
REPOSITORIES: biostudies-literature
Publications
Multiset Statistics for Gene Set Analysis.
Newton Michael A MA Wang Zhishi Z
Annual review of statistics and its application 20150401
An important data analysis task in statistical genomics involves the integration of genome-wide gene-level measurements with preexisting data on the same genes. A wide variety of statistical methodologies and computational tools have been developed for this general task. We emphasize one particular distinction among methodologies, namely whether they process gene sets one at a time (uniset) or simultaneously via some multiset technique. Owing to the complexity of collections of gene sets, the mu ...[more]
Similar Datasets
Project description:Historically, the majority of statistical association methods have been designed assuming availability of SNP-level information. However, modern genetic and sequencing data present new challenges to access and sharing of genotype-phenotype datasets, including cost of management, difficulties in consolidation of records across research groups, etc. These issues make methods based on SNP-level summary statistics particularly appealing. The most common form of combining statistics is a sum of SNP-level squared scores, possibly weighted, as in burden tests for rare variants. The overall significance of the resulting statistic is evaluated using its distribution under the null hypothesis. Here, we demonstrate that this basic approach can be substantially improved by decorrelating scores prior to their addition, resulting in remarkable power gains in situations that are most commonly encountered in practice; namely, under heterogeneity of effect sizes and diversity between pairwise LD. In these situations, the power of the traditional test, based on the added squared scores, quickly reaches a ceiling, as the number of variants increases. Thus, the traditional approach does not benefit from information potentially contained in any additional SNPs, while our decorrelation by orthogonal transformation (DOT) method yields steady gain in power. We present theoretical and computational analyses of both approaches, and reveal causes behind sometimes dramatic difference in their respective powers. We showcase DOT by analyzing breast cancer and cleft lip data, in which our method strengthened levels of previously reported associations and implied the possibility of multiple new alleles that jointly confer disease risk.
| S-EPMC7182280 | biostudies-literature
Project description:Differential expression (DE) analysis and gene set enrichment (GSE) analysis are commonly applied in single cell RNA sequencing (scRNA-seq) studies. Here, we develop an integrative and scalable computational method, iDEA, to perform joint DE and GSE analysis through a hierarchical Bayesian framework. By integrating DE and GSE analyses, iDEA can improve the power and consistency of DE analysis and the accuracy of GSE analysis. Importantly, iDEA uses only DE summary statistics as input, enabling effective data modeling through complementing and pairing with various existing DE methods. We illustrate the benefits of iDEA with extensive simulations. We also apply iDEA to analyze three scRNA-seq data sets, where iDEA achieves up to five-fold power gain over existing GSE methods and up to 64% power gain over existing DE methods. The power gain brought by iDEA allows us to identify many pathways that would not be identified by existing approaches in these data.
| S-EPMC7101316 | biostudies-literature
Project description:Small sample sizes combined with high person-to-person variability can make it difficult to detect significant gene expression changes from transcriptional profiling studies. Subtle, but coordinated, gene expression changes may be detected using gene set analysis approaches. Meta-analysis is another approach to increase the power to detect biologically relevant changes by integrating information from multiple studies. Here, we present a framework that combines both approaches and allows for meta-analysis of gene sets. QuSAGE meta-analysis extends our previously published QuSAGE framework, which offers several advantages for gene set analysis, including fully accounting for gene-gene correlations and quantifying gene set activity as a full probability density function. Application of QuSAGE meta-analysis to influenza vaccination response shows it can detect significant activity that is not apparent in individual studies.
| S-EPMC6461294 | biostudies-literature
Project description:BackgroundIdentifying sets of related genes (gene sets) that are empirically associated with a treatment or phenotype often yields valuable biological insights. Several methods effectively identify gene sets in which individual genes have simple monotonic relationships with categorical, quantitative, or censored event-time variables. Some distance-based methods, such as distance correlations, may detect complex non-monotone associations of a gene-set with a quantitative variable that elude other methods. However, the distance correlations have yet to be generalized to associate gene-sets with categorical and censored event-time endpoints. Also, there is a need to determine which genes empirically drive the significance of an association of a gene set with an endpoint.ResultsWe develop gene-set distance analysis (GSDA) by generalizing distance correlations to evaluate the association of a gene set with categorical and censored event-time variables. We also develop a backward elimination procedure to identify a subset of genes that empirically drive significant associations. In simulation studies, GSDA more effectively identified complex non-monotone gene-set associations than did six other published methods. In the analysis of a pediatric acute myeloid leukemia (AML) data set, GSDA was the only method to discover that event-free survival (EFS) was associated with the 56-gene AML pathway gene-set, narrow that result down to 5 genes, and confirm the association of those 5 genes with EFS in a separate validation cohort. These results indicate that GSDA effectively identifies and characterizes complex non-monotonic gene-set associations that are missed by other methods.ConclusionGSDA is a powerful and flexible method to detect gene-set association with categorical, quantitative, or censored event-time variables, especially to detect complex non-monotonic gene-set associations. Available at https://CRAN.R-project.org/package=GSDA .
| S-EPMC8059024 | biostudies-literature
Project description:BACKGROUND: Different microarray studies have compiled gene lists for predicting outcomes of a range of treatments and diseases. These have produced gene lists that have little overlap, indicating that the results from any one study are unstable. It has been suggested that the underlying pathways are essentially identical, and that the expression of gene sets, rather than that of individual genes, may be more informative with respect to prognosis and understanding of the underlying biological process. RESULTS: We sought to examine the stability of prognostic signatures based on gene sets rather than individual genes. We classified breast cancer cases from five microarray studies according to the risk of metastasis, using features derived from predefined gene sets. The expression levels of genes in the sets are aggregated, using what we call a set statistic. The resulting prognostic gene sets were as predictive as the lists of individual genes, but displayed more consistent rankings via bootstrap replications within datasets, produced more stable classifiers across different datasets, and are potentially more interpretable in the biological context since they examine gene expression in the context of their neighbouring genes in the pathway. In addition, we performed this analysis in each breast cancer molecular subtype, based on ER/HER2 status. The prognostic gene sets found in each subtype were consistent with the biology based on previous analysis of individual genes. CONCLUSIONS: To date, most analyses of gene expression data have focused at the level of the individual genes. We show that a complementary approach of examining the data using predefined gene sets can reduce the noise and could provide increased insight into the underlying biological pathways.
| S-EPMC2895626 | biostudies-literature
Project description:Gene-set analysis aims to identify differentially expressed gene sets (pathways) by a phenotype in DNA microarray studies. We review here important methodological aspects of gene-set analysis and illustrate them with varying performance of several methods proposed in the literature. We emphasize the importance of distinguishing between 'self-contained' versus 'competitive' methods, following Goeman and Bühlmann. We also discuss reducing a gene set to its subset, consisting of 'core members' that chiefly contribute to the statistical significance of the differential expression of the initial gene set by phenotype. Significance analysis of microarray for gene-set reduction (SAM-GSR) can be used for an analytical reduction of gene sets to their core subsets. We apply SAM-GSR on a microarray dataset for identifying biological gene sets (pathways) whose gene expressions are associated with p53 mutation in cancer cell lines. Codes to implement SAM-GSR in the statistical package R can be downloaded from http://www.ualberta.ca/~yyasui/homepage.html.
| S-EPMC2638622 | biostudies-literature
Project description:Gene set analysis (GSA) has become a successful tool to interpret gene expression profiles in terms of biological functions, molecular pathways, or genomic locations. GSA performs statistical tests for independent microarray samples at the level of gene sets rather than individual genes. Nowadays, an increasing number of microarray studies are conducted to explore the dynamic changes of gene expression in a variety of species and biological scenarios. In these longitudinal studies, gene expression is repeatedly measured over time such that a GSA needs to take into account the within-gene correlations in addition to possible between-gene correlations.We provide a robust nonparametric approach to compare the expressions of longitudinally measured sets of genes under multiple treatments or experimental conditions. The limiting distributions of our statistics are derived when the number of genes goes to infinity while the number of replications can be small. When the number of genes in a gene set is small, we recommend permutation tests based on our nonparametric test statistics to achieve reliable type I error and better power while incorporating unknown correlations between and within-genes. Simulation results demonstrate that the proposed method has a greater power than other methods for various data distributions and heteroscedastic correlation structures. This method was used for an IL-2 stimulation study and significantly altered gene sets were identified.The simulation study and the real data application showed that the proposed gene set analysis provides a promising tool for longitudinal microarray analysis. R scripts for simulating longitudinal data and calculating the nonparametric statistics are posted on the North Dakota INBRE website http://ndinbre.org/programs/bioinformatics.php. Raw microarray data is available in Gene Expression Omnibus (National Center for Biotechnology Information) with accession number GSE6085.
| S-EPMC3142525 | biostudies-literature
Project description:We present a comprehensive and efficient gene set analysis tool, called 'GeneTrail' that offers a rich functionality and is easy to use. Our web-based application facilitates the statistical evaluation of high-throughput genomic or proteomic data sets with respect to enrichment of functional categories. GeneTrail covers a wide variety of biological categories and pathways, among others KEGG, TRANSPATH, TRANSFAC, and GO. Our web server provides two common statistical approaches, 'Over-Representation Analysis' (ORA) comparing a reference set of genes to a test set, and 'Gene Set Enrichment Analysis' (GSEA) scoring sorted lists of genes. Besides other newly developed features, GeneTrail's statistics module includes a novel dynamic-programming algorithm that improves the P-value computation of GSEA methods considerably. GeneTrail is freely accessible at http://genetrail.bioinf.uni-sb.de.
| S-EPMC1933132 | biostudies-literature
Project description:Assessing functional associations between an experimentally derived gene or protein set of interest and a database of known gene/protein sets is a common task in the analysis of large-scale functional genomics data. For this purpose, a frequently used approach is to apply an over-representation-based enrichment analysis. However, this approach has four drawbacks: (i) it can only score functional associations of overlapping gene/proteins sets; (ii) it disregards genes with missing annotations; (iii) it does not take into account the network structure of physical interactions between the gene/protein sets of interest and (iv) tissue-specific gene/protein set associations cannot be recognized.To address these limitations, we introduce an integrative analysis approach and web-application called EnrichNet. It combines a novel graph-based statistic with an interactive sub-network visualization to accomplish two complementary goals: improving the prioritization of putative functional gene/protein set associations by exploiting information from molecular interaction networks and tissue-specific gene expression data and enabling a direct biological interpretation of the results. By using the approach to analyse sets of genes with known involvement in human diseases, new pathway associations are identified, reflecting a dense sub-network of interactions between their corresponding proteins.EnrichNet is freely available at http://www.enrichnet.org.Natalio.Krasnogor@nottingham.ac.uk, reinhard.schneider@uni.lu or avalencia@cnio.esSupplementary data are available at Bioinformatics Online.
| S-EPMC3436816 | biostudies-other
Project description:Enrichment analysis of gene sets is a popular approach that provides a functional interpretation of genome-wide expression data. Existing tests are affected by inter-gene correlations, resulting in a high Type I error. The most widely used test, Gene Set Enrichment Analysis, relies on computationally intensive permutations of sample labels to generate a null distribution that preserves gene-gene correlations. A more recent approach, CAMERA, attempts to correct for these correlations by estimating a variance inflation factor directly from the data. Although these methods generate P-values for detecting gene set activity, they are unable to produce confidence intervals or allow for post hoc comparisons. We have developed a new computational framework for Quantitative Set Analysis of Gene Expression (QuSAGE). QuSAGE accounts for inter-gene correlations, improves the estimation of the variance inflation factor and, rather than evaluating the deviation from a null hypothesis with a P-value, it quantifies gene-set activity with a complete probability density function. From this probability density function, P-values and confidence intervals can be extracted and post hoc analysis can be carried out while maintaining statistical traceability. Compared with Gene Set Enrichment Analysis and CAMERA, QuSAGE exhibits better sensitivity and specificity on real data profiling the response to interferon therapy (in chronic Hepatitis C virus patients) and Influenza A virus infection. QuSAGE is available as an R package, which includes the core functions for the method as well as functions to plot and visualize the results.
| S-EPMC3794608 | biostudies-literature